1. Technical Field
The present invention relates to a nitrogen-containing tricyclic compound useful as a medicine, a medicine containing the same and processes for producing the same. More particularly, it relates to a novel nitrogen-containing tricyclic compound useful as a medicine for diseases against which the effect of inhibiting the binding of IgE receptor xcex3 to a tyrosine kinase of 72 kDa is efficacious.
2. Prior Art
The bronchial asthma and the atopic diseases in human beings appear in consequence of highly intriacate vital reactions. It is suspected that most of these conditions are caused because various chemical mediators liberated from mast cells and basophils, as triggered by antigen-antibody reactions, induce vital disturbances as by contracting such smooth muscles as bronchial muscles and vessels of the pulmonary circulation or enhancing permeability of blood vessels.
As the chemical mediators liberated from mast cells and basophils, histamine, leukotrienes, prostaglandins, TNF, etc. have been known. It is well known that histamine, among other substances mentioned above, is the most significant chemical mediator for the allergic rhinitis and the urticaria in human beings. The leucotrienes comprise leucotrienes B4, C4, and D4 and the relation thereof with the asthmatic convulsion has been attracting attention.
Heretofore, the development of medicines for the prevention, alleviation, or elimination of the crisis of symptoms of allergic diseases has been aimed at repressing the creation and liberation of such chemical mediators or antagonizing the effects thereof.
Sodium cromoglycate (Intal(trademark)) having been marketed since 1969 is a typical example of these drugs.
However, the conventional antiallergic agents typified by Intal(trademark) show difference in the chemical mediator liberation inhibitory concentration between in vitro and in vivo. Moreover, sensitivities to these drugs widely vary from patient to patient and their action mechanisms still remain unknown in many points.
Mast cells and basophils closely relating to allergic diseases have a highly affinitive receptor, Fcxcex5 RI, for the IgE antibody on the cell membrane thereof. IgE antibody""s binding to this receptor forms a cross-linkage with the corresponding polyvalent antigen, the intracellular signal transmission mechanism is activated. Then histamine is liberated or leukotrienes and prostaglandins are formed and liberated, thus inducing the onset of the so-called allergic symptoms. It is furthermore considered that the cytokines such as TNF and interleukins thus produced interact with other cells and thus make the diseases chronic.
Under these circumstances, the present inventors have paid their attention to the activation of a non-receptor type tyrosine kinase located at the early stage in the activation of the intracellular signal transmission mechanism upon liberation of chemical mediators from mast cells or basophils. It is known that this tyrosine kinase is activated when it binds to the phosphorylated tyrosine activation motif (TAM) region in the IgE receptor xcex3 chain. By inhibiting this binding to thereby inhibit the activation of the tyrosine kinase of 72 kDa, the activation of the intracellular signal transmission mechanism depending on the IgE antibody in mast cells or basophils can be inhibited. As a result, also the liberation of the above chemical mediators can be inhibited. The present inventors have found out that desired objects can be achieved by using nitrogen-containing tricyclic compounds represented by the following formula (I), thus completing the present invention.
An object of the present invention is to provide a novel acridone derivative and a pharmacologically acceptable salt thereof which is efficacious in preventing or treating asthma, allergic rhinitis, atopic dermatitis, urticaria, hay fever, gastrointestinal allergy, food allergy, etc. Another object of the present invention is to provide a medicine containing as the active ingredient the compound, a hydrate thereof or a pharmacologically acceptable salt thereof.
Accordingly, the present invention relates to a nitrogen-containing tricyclic compound represented by the following formula (I), a hydrate thereof or a pharmacologically acceptable salt thereof: 
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are the same or different from each other and each represents hydrogen, hydroxy, cyano, nitro, optionally substituted carbamoyl, halogeno, optionally halogenated lower alkyl, optionally substituted cycloalkyl, optionally halogenated lower alkoxy, acyl, optionally protected carboxy, optionally substituted aryl, optionally substituted heteroaryl, cycloalkylalkyl, hydroxylated alkyl, alkoxyalkyl, optionally protected carboxyalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, cyanoalkyl, acylalkyl, optionally substituted carbamoylalkyl, optionally halogenated alkenyl, hydroxyalkenyl, alkoxyalkenyl, optionally protected carboxyalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionally substituted carbamoylalkenyl, optionally halogenated alkynyl, hydroxyalkynyl, alkoxyalkynyl, optionally protected carboxyalkynyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, cyanoalkynyl, acylalkynyl, optionally substituted carbamoylalkynyl, hydroxyalkoxy, alkoxyalkoxy, optionally protected carboxyalkoxy, optionally substituted arylalkoxy, optionally substituted heteroarylalkoxy, xe2x80x94Axe2x80x94NR9R10 [wherein A represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or a single bond; and R9 and R10 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl, optionally substituted aryl or acyl, or R9 and R10 may form together with the nitrogen atom to which they are bonded a ring optionally having additional nitrogen, oxygen or sulfur], or 
[wherein B represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or a single bond; R11 represents optionally halogenated lower alkyl or amino optionally substituted by lower alkyl; and x represents an integer of from 0 to 2];
provided that two of R1, R2, R3, R4, R5, R6, R7 and R8 adjacent to each other may form together with the carbon atom to which they are bonded a ring optionally containing oxygen, sulfur or nitrogen and optionally substituted;
z represents 
[wherein y represents an integer of from 0 to 2], 
[wherein y represents an integer of from 0 to 2],
[wherein R12, R13, R14, R15, R16 and R17 are the same or different from each other and each represents hydrogen, optionally substituted carbamoyl, optionally halogenated lower alkyl, optionally substituted cycloalkyl, acyl, optionally halogenated lower alkylsulfonyl, optionally substituted arylsulfonyl, optionally protected carboxy, optionally substituted aryl, optionally substituted heteroaryl, cycloalkylalkyl, hydroxylated alkyl, alkoxyalkyl, optionally protected carboxyalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, cyanoalkyl, acylalkyl, optionally substituted carbamoylalkyl, optionally halogenated alkenyl, hydroxyalkenyl, alkoxyalkenyl, optionally protected carboxyalkenyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, cyanoalkenyl, acylalkenyl, optionally substituted carbamoylalkenyl, optionally halogenated alkynyl, hydroxyalkynyl, alkoxyalkynyl, optionally protected carboxyalkynyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, cyanoalkynyl, acylalkynyl, optionally substituted carbamoylalkynyl, xe2x80x94Wxe2x80x94NR18R19 (wherein W represents optionally branched alkylene, optionally branched alkenylene, optionally branched alkynylene or a single bond; R18 and R19 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl or acyl, or R18 and R19 may form together with the nitrogen atom to which they are bonded a ring optionally containing additional nitrogen, oxygen or sulfur)];
D represents optionally substituted alkylene, optionally substituted alkenylene, optionally substituted alkynylene or 
(wherein m and l are each an integer of from 0 to 6; the ring A means an optionally substituted hydrocarbon ring or an optionally substituted heterocycle); and
Q represents optionally substituted carbamoyl, acyl, acylalkyl, optionally protected carboxy, optionally substituted heteroaryl, or xe2x80x94NR20R21 (wherein R20 and R21 are the same or different from each other and each represents hydrogen, optionally halogenated lower alkyl, optionally halogenated lower alkoxy, hydroxylated alkyl, alkoxyalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally protected carboxyalkyl, acyl, optionally substituted acylalkyl, optionally substituted acylamino, optionally substituted acylaminoalkyl, cyanoalkyl, optionally substituted carbamoylalkyl, optionally substituted aminoalkyl, cyanoalkyl, acylalkyl, cycloalkyl, cycloalkylalkyl or amidino optionally substituted by lower alkyl, or R20 and R21 may form together with the nitrogen atom to which they are bonded an optionally substituted 3- to 8-membered ring which may have, as its ring-member other than carbon, at least one member selected from the group consisting of nitrogen, sulfur, oxygen and xe2x80x94NR22 (wherein R22 represents hydrogen, optionally halogenated lower alkyl, acyl, optionally substituted acylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or xe2x80x94S(O)sxe2x80x94(Y)uxe2x80x94R23 (wherein R23 represents hydrogen, optionally halogenated lower alkyl or optionally substituted aryl; Y represents methylene; s is an integer of from 0 to 2; and u is 0 or 1))];
provided that the following cases are excluded:
(1) the one where R5 and R6 are both hydrogen atoms;
(2) the one where Z is 
[wherein y is an integer of from 0 to 2]; R5 is fluoro; and R6 is fluoro or trifluoromethyl; and
(3) the one where Z is 
[wherein y is an integer of from 0 to 2]; R5 is carboxy; and R6 is chloro}.
The term xe2x80x9chalogen atomxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8in the formula (I) means fluorine, chlorine, bromine, iodine, etc.
The term xe2x80x9clower alkylxe2x80x9d in xe2x80x9coptionally halogenated lower alkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and R23 means linear or branched C1-6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2-ethylpropyl, n-hexyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1-ethyl-2-methylpropyl and 1-methyl-2-ethylpropyl groups.
In such a case, the term xe2x80x9coptionally halogenatedxe2x80x9d means that the above alkyl may be substituted by 1 to 3 halogen atoms such as fluorine, chlorine, bromine or iodine. Namely, the xe2x80x9coptionally halogenated lower alkylxe2x80x9d as used in the formula (I) includes trifluoromethyl, dibromoethyl and the like.
The term xe2x80x9clower alkenylxe2x80x9d in xe2x80x9coptionally halogenated lower alkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R20 and R21 means linear or branched C1-6 alkenyl, for example, vinyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, 1-butenyl, 2-butenyl and 3-butenyl groups. The lower alkenyl as used herein further includes the above-mentioned alkenyl substituted by 1 to 3 halogen atoms.
The term xe2x80x9clower alkynylxe2x80x9d in xe2x80x9coptionally halogenated lower alkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means linear or branched C1-6 alkynyl, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-propynyl and 2-methyl-3-propynyl groups. The lower alkynyl as used herein further includes the above-mentioned alkynyl substituted by 1 to 3 halogen atoms.
The term xe2x80x9ccycloalkylxe2x80x9d in xe2x80x9coptionally substituted cycloalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means C3-8 ones such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein the above lower alkyl is attached to any carbon atom of the above cycloalkyl.
The term xe2x80x9clower alkoxyxe2x80x9d in xe2x80x9coptionally halogenated lower alkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R20 and R21 means linear or branched C16 alkoxy, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, 1,2-dimethylpropyloxy, 1,1-dimethylpropyloxy, 2,2-dimethylpropyloxy, 2-ethylpropyloxy, n-hexyloxy, 1,2-dimethylbutyloxy, 2, 3-dimethylbutyloxy, 1,3-dimethylbutyloxy, 1-ethyl-2-methylpropyloxy and 1-methyl-2-ethylpropyloxy groups.
In such a case, the term xe2x80x9coptionally halogenatedxe2x80x9d means that the above alkoxy may be substituted by 1 to 3 halogen atoms such as fluorine, chlorine, bromine or iodine. Namely, the xe2x80x9coptionally halogenated lower alkoxyxe2x80x9d as used herein includes trifluoromethoxy, dibromoethoxy and the like.
The term xe2x80x9cacylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22 and Q means those derived from saturated aliphatic monocarboxylic acids such as acetyl, propionyl, butyryl, valeryl, isovaleryl and pivaloyl groups, those derived from unsaturated aliphatic carboxylic acids such as acryloyl, propioloyl, methacryloyl, crotonoyl and isocrotonoyl groups, those derived from carbocyclic carboxylic acids such as benzoyl, naphthoyl, toluoyl, hydroatropoyl, atropoyl and cinnamoyl groups, those derived from heterocyclic carboxylic acids such as furoyl, thenoyl, nicotinoyl and isonicotinoyl groups, those derived from hydroxy carboxylic acids or alkoxy carboxylic acids such as glycoloyl, lactoyl, glyceroyl, tropoyl, benzyloyl, salicyloyl, anisoyl, vaniloyl, piperonyloyl and galloyl groups and those derived from various amino acids.
The term xe2x80x9cacylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R12, R13, R14, R15, R16, R17, R20, R21, R22 and Q means those wherein the above acyl is attached to any carbon atom of the above lower alkyl. Examples thereof include acetylmethyl, propionylmethyl, benzoylethyl, naphthoylpropyl, cinnamoylpropyl, salicyloylbutyl, nicotinoylpentyl and glyceroylhexyl groups, though, needless to say, the present invention is not restricted thereto.
The term xe2x80x9cacylalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the acyl is attached to any carbon atom of the above alkenyl. Examples thereof include benzoyl-1-ethylenyl and 3-nicotinoyl-2-propylenyl, though, needless to say, the present invention is not restricted thereto.
The term xe2x80x9cacylalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the acyl is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9chydroxylated alkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein 1 to 3 hydroxyl groups are attached to any carbon atom of the above lower alkyl, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl and 3,4-dihydroxybutyl groups.
The term xe2x80x9chydroxyalkenylxe2x80x9d as used in the definition of
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein hydroxy is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9chydroxyalkynylxe2x80x9d as used in the definition of
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, 13, R14, R15, R16 and R17 means those wherein hydroxy is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9calkoxyalkylxe2x80x9d as used in the definition of R1, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkyl, for example, methoxymethyl, ethoxymethyl, ethoxyethyl and 2-ethoxypropyl groups, though the present invention is not restricted thereto.
The term xe2x80x9calkoxyalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkenyl, for example, methoxyethylenyl and ethoxypropylenyl groups, though the present invention is not restricted thereto.
The term xe2x80x9calkoxyalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16 and R17 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9ccyanoalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21, R22 and R23 means those wherein cyano is attached to any carbon atom of the above lower alkyl, for example, cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 1-cyanopropyl and 2-cyanopropyl groups.
The term xe2x80x9ccyanoalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein cyano is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9ccyanoalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein cyano is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9chydroxyalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein hydroxy is attached to any carbon atom of the above lower alkoxy, for example, hydroxymethoxy, 1-hydroxyethoxy, 2-hydroxyethoxy, 1-hydroxypropoxy, 2-hydoxypropoxy and 3-hydroxypropoxy groups.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7 and R8 means those wherein the above lower alkoxy is attached to any carbon atom of the above lower alkoxy, for example, methoxymethoxy, 1-methoxyethoxy, 2-methoxyethoxy, ethoxymethoxy, 1-ethoxyethoxy, 2-ethoxyethoxy, 1-methoxypropoxy and 2-methoxypropoxy groups.
The term xe2x80x9carylxe2x80x9d in xe2x80x9coptionally substituted arylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, R17, R20, R21, R22 and R23 means, for example, phenyl, 1-naphthyl, 2-naphthyl and anthracenyl groups.
The term xe2x80x9carylxe2x80x9d in xe2x80x9coptionally substituted arylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21 and R22 has the same meaning as the one defined above. In such a case, the term xe2x80x9calkylxe2x80x9d has the same meaning as that of xe2x80x9clower alkylxe2x80x9d defined above.
The term xe2x80x9coptionally substituted heteroarylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21, R22 and Q means those derived from single or fused rings containing 1 to 4 heteroatoms of at least one type selected from the group consisting of sulfur, oxygen and nitrogen atoms. Examples thereof include pyrrolyl, thienyl, furyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzothienyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazyl, quinoxalyl, naphthyridyl, quinazolyl and imidazopyridyl groups.
The term xe2x80x9coptionally substituted heteroarylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21 and R22 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkyl.
The term xe2x80x9coptionally substituted heteroarylalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkenyl.
The term xe2x80x9coptionally substituted heteroarylalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein the above heteroaryl is attached to any carbon atom of the above lower alkynyl.
The term xe2x80x9coptionally substituted carbamoylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17 and Q means carbamoyl optionally having 1 or 2 substituents on the nitrogen atom.
The terms xe2x80x9coptionally substituted carbamoylalkyl, carbamoylalkenyl and carbamoylalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 mean those wherein optionally substituted carbamoyl is attached to any carbon atom of the above lower alkyl, alkenyl and alkynyl.
Examples of the substituents in the optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted arylalkenyl, optionally substituted heteroarylalkenyl, optionally substituted arylalkynyl, optionally substituted heteroarylalkynyl, optionally substituted arylalkoxy, optionally substituted heteroarylalkoxy, optionally substituted carbamoyl, optionally substituted carbamoylalkyl, optionally substituted carbamoylalkenyl and optionally substituted carbamoylalkynyl include hydroxy; lower alkyl such as methyl, ethyl, n-propyl and isopropyl; lower alkoxy such as methoxy, ethoxy, n-propoxy and isopropoxy; halogen atom such as fluorine, chlorine, bromine and iodine; cyano; acyl such as acetyl, propionyl and benzoyl; amino; nitro: optionally protected carboxyl; carbamoyl; acylamino; sulfamoyl; alkylsulfonylamino; arylsulfonylamino; heteroaryl; carboxyalkyl; carboxyalkoxy; heteroarylalkyl; heteroarylalkoxy; methylenedioxy; and ethylenedioxy. The substituents are selected therefrom.
Examples of the protective groups in the xe2x80x9coptionally protected carboxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20, R21 and Q include lower alkyl such as methyl, ethyl and tert-butyl; lower alkyl substituted by optionally substituted phenyl such as p-methoxybenzyl, p-nitrobenyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and phenethyl; halogenated lower alkyl such as 2,2,2-trichloroethyl and 2-iodoethyl; lower alkanoyloxy-substituted lower alkyl such as pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, varelyloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, 1-pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy-substituted lower alkyl such as palmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl; lower alkoxycarbonyloxy-substituted lower alkyl such as methoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and 1-(isopropoxycarbonyloxy)ethyl; carboxy-substituted lower alkyl such as carboxymethyl and 2-carboxyethyl; benzoyloxy-substituted lower alkyl optionally substituted by heteroaryl such as 3-phthalidyl, 4-glycyloxybenzoyloxymethyl, etc.;
(substituted dioxolene)-substituted lower alkyl such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl; cycloalkyl-substituted lower alkanoyloxy-substituted lower alkyl such as 1-cyclohexylacetyloxyethyl; and cycloalkyloxycarbonyloxy-substituted lower alkyl such as 1-cyclohexyloxycarbonyloxyethyl. Moreover, various acid amides are also usable therefor. In summary, the carboxy-protective group may be an arbitrary one, so long as it is decomposed by some means to give a carboxylic acid in vivo.
The term xe2x80x9coptionally protected carboxylalkylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein carboxy optionally having the above protective group(s) is attached to any carbon atom of the above lower alkyl.
The term xe2x80x9coptionally protected carboxylalkoxyxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16, R17, R20 and R21 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkoxy. In such a case, the protective group has the same meaning as the one defined above.
The term xe2x80x9coptionally protected carboxyalkenylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkenyl. In such a case, the protective group has the same meaning as the one defined above.
The term xe2x80x9coptionally protected carboxyalkynylxe2x80x9d as used in the definition of R1, R2, R3, R4, R5, R6, R7, R8, R12, R13, R14, R15, R16 and R17 means those wherein optionally protected carboxy is attached to any carbon atom of the above lower alkynyl. In such a case, the protective group has the same meaning as the one defined above.
Examples of the ring in xe2x80x9cR20 and R21 may form together with the nitrogen atom to which they are bonded a ringxe2x80x9d of the formula xe2x80x94NR20R21 as used in the definition of Q include aziridine, azetidine, pyrrolidine, piperidine, perhydroazepine, perhydroazocine, piperazine, homopiperazine, morpholine, thiomorpholine, thiomorpholine dioxide, indoline, isoindoline, 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihdyrobenzoxazine, 2,3-dihydrobenzothiazine, pyrrole, imidazole, pyrazole, triazole, tetrazole, indole, isoindole, indazole and benzotriazole.
(a) The term xe2x80x9calkylenexe2x80x9d as used in the definition of A, B and W means methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene.
(b) The term xe2x80x9calkenylenexe2x80x9d as used in the definition of A , B and W means ethenylene, propenylene, butenylene, pentenylene, hexenylene, butanedienylene, pentanedienylene, hexanedienylene or hexanetrienylene.
(c) The term xe2x80x9calkynylenexe2x80x9d as used in the definition of A, B and W means ethynylene, propynylene, butynylene, pentynylene, hexynylene, butanediynylene, pentanediynylene, hexanediynylene or hexanetriynylene.
(d) The term xe2x80x9chydrocarbon ringxe2x80x9d as used in the definition of the ring A means cyclopropane, cyclobutane, cyclopentane, cyclohexane, benzene, naphthalene, etc.
(e) The term xe2x80x9cheterocyclexe2x80x9d as used in the definition of the ring A means pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, homopiperazine, pyrrole, pyrazole, imidazole, triazole, tetrazole, oxazole, thiazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, imidazopyridine, quinoline, naphthyridine, phthalazine, etc.
In the case of the compounds of the present invention having asymmetric carbon atoms, it is needless to say that the optical isomers thereof are also included in the scope of the present invention. Furthermore, hydrates thereof are included in the scope of the present invention.
Examples of the pharmacologically acceptable salts as used in the present invention include inorganic acid salts such as hydrochlorides, hydrobromides, sulfates and phosphates; organic acid salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates and toluenesulfonates; and salts of amino acids such as aspartic and glutamic acids.
To facilitate the understanding of the present invention, and not by way of limitation, typical examples of the compounds of the present invention will be given. Each compound is expressed in a free state:
1) 1,2-dimethyl-10-[3-[(2-hydroxy-3-methylphenyl)methylamino]propyl]phenothiazine-5-dioxide
2) 1,2-dimethyl-10-[3-[(3-chloro-2-hydroxyphenyl)methylamino]propyl]phenothiazine-5-dioxide
3) 1,2-dimethyl-10-[3-[(5-methoxy-2-furanyl)methylamino]propyl]phenothiazine-5-dioxide
4) 1,2-dimethyl-10-[3-[(3-methoxy-2-thienyl)methylamino]propyl]phenothiazine-5-dioxide
5) 1,2-dimethyl-10-[3-(4-hydroxy-4-phenylpiperidinyl)propyl]phenothiazine-5-dioxide
6) 1,2-dimethyl-10-[3-(4-benzylpiperazinyl)propyl]phenothiazine-5-dioxide
7) 1,2-dimethyl-10-[3-[N-[(2-hydroxyphenyl)methyl]methylamino]propyl]-phenothiazine-5-dioxide
8) 1,2-dimethyl-10-[3-[N-[(2-hydroxy-3-methylphenyl)methyl]methylamino]propyl]-phenothiazine-5-dioxide
9) (E,Z)-3,4-dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-(2-carboxyethyl) ether
10) (E,Z)-3,4-dimethyl-10-(3-benzylaminopropyl)-9-acridoneoxime-O-(1-carboxyethyl) ether.
The compounds of the present invention can be produced by combining generally known methods. Now, main processes generally usable for producing the compounds of the present invention will be illustrated.
Compounds of the formula (I) wherein Z is xe2x80x94S(O)yxe2x80x94 and Q is xe2x80x94NR20R21 can be produced by the following process. 
i) A phenothiazine derivative represented by the formula (II) synthesized by a publicly known method [for example, those described in J. Org. Chem., 20, 1577 (1955).; ibid., 35, 4254 (1970).; J. Chem. Soc., (C) 2437 (1970).; and Chem. Ind., 238 (1966).] is reacted in the presence of a base with a compound represented by the formula (III) having leaving groups at both ends to thereby give a phenothiazine derivative represented by the formula (IV). Preferable examples of the base usable herein include sodium hydride, n-butyllithium and t-butoxypotassium. Preferable examples of the leaving groups include halogeno and sulfonate. Any reaction solvent may be used therefor, so long as it remains inert during the reaction. Next, the leaving group Lxe2x80x2 in the compound (IV) is substituted by phthalimide. The resulting phthalimide compound represented by the formula (V) is then treated with hydrazine hydrate to give an amine compound represented by the general formula (VI). Next, this amine compound (VI) is condensed under dehydration with an aldehyde compound (VII: wherein R represents alkyl, alkenyl, alkynyl, aryl or heteroaryl). The Schiff base thus obtained is then treated with a reducing agent such as sodium borohydride to give analkylamine compound represented by the formula (VIII). Any reaction solvent may be used therefor, so long as it remains inert during the reaction.
Alternatively, the phthalimide compound (V) serving as an intermediate may be synthesized in the following manner. Namely, the compound (II) is reacted with a compound having a leaving group L at one end and a protected hydroxyl group at another end to give a compound represented by the formula (IVxe2x80x2). Subsequently, the compound (IVxe2x80x2) is deblocked in a conventional manner to give an alcohol (IVxe2x80x3), which is then reacted with phthalimide under the conditions of the Mitsunobu reaction to give a phthalimide compound.
ii) The compound (IV) is treated with a primary or secondary amine, or the compound (VI) is treated with a compound having a leaving group L (IX and/or Xxe2x80x2) to give a compound represented by the formula (X).
iii) A sulfoxide compound (XI) and a sulfonyl compound (XII) can be produced by oxidizing the sulfur atoms in the compounds (VIII) and (IX) or oxidizing the sulfur atom in the stage of the intermediate (IV) or (VI) in the process of the above i) or ii) followed by appropriate reactions.
Compounds of the formula (I) wherein Z is xe2x80x94C(=NOR12)xe2x80x94 or xe2x80x94C(=NNR13R14) and Q is xe2x80x94NR20R21 can be produced by the following process. 
An acridone compound (XIII) synthesized by a publicly known method (for example, the one described in JP-A 7-3161359) is reacted with a compound (III) to give a compound (XIV). Next, this compound (XIV) is reacted with potassium phthalimide to give a compound (XV). Then the compound (XV) is reacted with oxalyl chloride. The acridinium salt thus obtained is reacted with a hydroxylamine derivative (R12ONH2: wherein R12 is as defined above) or a hydrazine derivative (R13R14NNH2: wherein R13 and R14 are each as defined above) to give a compound represented by the formula (XVI) or (XVIxe2x80x2). Then the obtained compound is reacted with hydrazine hydrate to give a primary amine compound represented by the formula (XVII) or (XVIIxe2x80x2). Further, secondary or tertiary amines can be produced in accordance with the methods of i) of ii) in the above production process 1.
Compounds represented by the formula (I) wherein Z is xe2x80x94C(=CR16R17)xe2x80x94 and Q is xe2x80x94NR20R21 can be produced by the following process. 
The compound represented by the formula (XIV) given in the production process 2 is reacted with a metal compound Mxe2x80x94CHR16R17 (wherein M means a metal and R16 and R17 are each as defined above such as alkyl lithium, etc.) to give an acridan compound represented by the formula (XVIII). Next, this product is treated in the same manner as the one described in the production process 1 ii) to give an amine compound represented by the formula (IX).
Compounds represented by the formula (I) wherein Z is xe2x80x94C(xe2x95x90O)N(R15)xe2x80x94 or xe2x80x94N(R15C(xe2x95x90O)xe2x80x94and Q is xe2x80x94NR20R21 can be produced by the following process. 
The procedure of the step i) or ii) in the production process 1 was repeated while replacing the phenothiazine derivative represented by the formula (II) employed in the production process 1 by a dibenzodiazepine derivative (XX or XXxe2x80x2) produced by a publicly known method [Indian J. Chem., 23B, 85 (1984).] or Production Example 13 or 14. Thus a compound represented by the formula (XXI or XXIxe2x80x2) can be obtained.
Compounds of the formula (I) wherein Q is heteroaryl can be produced by the following process. 
The compound represented by the formula (XXII) obtained by the production processes 1, 2, 3 and 4 and having a leaving group Lxe2x80x2 is treated with magnesium to give a Grignard reagent. Next, this Grignard reagent is reacted with an optionally substituted heteroaryl halide derived from, e.g., pyridine or pyrimidine in the presence of 1,3-bis(diphenylphosphino)propane nickel dichloride [Ni(dppp)Cl2] to give a compound represented by the formula (XXIV).
Compounds of the formula (I) wherein Q is optionally substituted carbamoyl, acyl or optionally protected carboxy can be produced by the following process. 
The compound represented by the formula (XXII) obtained by the production processes 1, 2, 3 and 4 and having a leaving group Lxe2x80x2 is treated with a reagent for cyanation such as sodium cyanide in the presence of a base to give a nitrile compound (XXV), which is then hydrolyzed to give an unsubstituted carbamoyl compound (XXVI) or an ester or carboxylic acid represented by the formula (XXVII). A substituted carbamoyl compound (XXVIII) can be obtained by alkylating or aralkylating the unsubstituted carbamoyl compound (XXVI) or reacting the ester or a reactive derivative (acid halide, reactive ester, etc.) derived from the carboxylic acid in a conventional manner with a primary or a secondary amine. A protected carboxyl compound can be obtained by reacting the reactive derivative derived from the carboxylic acid with an alcohol derivative.
To illustrate the usefulness of the present invention, pharmacological experimental examples will be given.
(1) Inhibitory Effects on Various Mediators Release from Rat Basophilic Leukemia Cell Line (RBL-2H3)
i) Experimental Method
IgE-sensitized RBL-2H3 cells (i.e., a cell line originating in rat cells) release and produce not only histamine and serotonin but also cytokines such as TNF xcex1 and prostaglandins which are inflammatory mediators after stimulation with IgE sepecific antibody. In this experimental system, inhibitory effects on various mediators release were examined by using serotonin as an indication.
The cells were beforehand labeled with [3H]-labeled serotonin and, at the same time, sensitized with the IgE antibody. After incubating with the compounds of the present invention, the cells were stimulated with the specific antigen. Then the inhibitory activity of each compound was calculated from the amount of the [3H]-labeled serotonin thus liberated into the medium and the amount of [3H]-labeled serotonin liberated when no compound of the present invention was added.
ii) Results of the Experiment
The results are shown in Tables 1 to 3.
The compound numbers correspond to Example Nos. as will be given hereinafter (the same will apply hereinafter).
(2) Inhibitory Effects on Various Mediators Release from Human Basophils
i) Experimental Method
6 ml of 6% dextran (for separating leukocytes, having a high molecular weight) was added to 20 ml of heparinized blood. After stirring well, the resulting mixture was allowed to stand at 37xc2x0 C. for 30 min and thus erythrocytes were precipitated. The upper layer was taken up and phosphate buffered saline (D-PBS) was added thereto followed by centrifugation at 185 g for 8 minutes to give a crude leukocyte fraction. These cells were subjected to hypotonic hematolysis and then suspended in D-PBS(+) containing 0.1%-BSA. The resulting suspension was used in the subsequent experiment as the leukocyte fraction containing basophils. 0.4 ml of this cell suspension was preliminarily heated to 37xc2x0 C. for 5 min and then 0.05 ml of a specimen solution was added thereto followed by a pretreatment at 37xc2x0 C. for 15 min. Next, 0.05 ml of a mite antigen solution was added thereto to induce an antigen-antibody reaction. After 10 min, the reaction was ceased by ice-cooling. Then the reaction mixture was centrifuged at 185 g for 10 min and histamine and peptide leukotrienes in the resulting supernatant were determined by using enzyme immunoassay kits. From the results of the assay, the activities of the acridone derivatives of inhibiting the liberation of histamine and peptide leukotriene were determined.
ii) Results of the Experiment
The results are given in Tables 4 to 7 wherein the term xe2x80x9cleukotrienexe2x80x9d means peptide leukotriene.
(3) Inhibitory Effects on the Interaction between IgE Receptor xcex3 Chain and 72 kDa Tyrosine Kinase
i) Experimental Method
RBL-2H3 cells which are a cell line generally used in studying IgE-mediated intracellular signal transduction in mast cells and basophils were used in this study. Tyrosine-phosphorylated peptide in the tyrosine activation motif (TAM) region in the IgE receptor xcex3 chain was synthesized by Peptide Institute.
In the experiment, cell lysates or cytosolic fraction of RBL-2H3 cells were used. Cell lysates were prepared by solubilizing 1xc3x97107 to 5xc3x97107 cells with a solution containing various protease inhibitors and 1%-NP-40 as a solubilizer. Separately, the cells were homogenized in a Downs homogenizer and centrifuged at 50,000 rpm for 1 hr, and the resulting supernatant was used as the cytosol fraction of the cells. The concentration of the lysate or cytosol was adjusted to 1 mg protein/ml with an isotonic buffer. The phosphorylation experiment of the 72 kDa tyrosine kinase contained in the lysate or cytosol was carried out in the following manner.
An assay buffer [150 mM NaCl, 10 mM KCl, 20 mM Tris (pH 7.5), 0.6 mM MnCl2, 0.5 mM EGTA, 5 mM NaF, 1 mM sodium pyrophosphate and 1 mM sodium orthovanadate] containing the lysate or cytosol in an amount corresponding to 10 mg of protein was incubated together with the compound 101 at 30xc2x0 C. for 3 min. After adding 50 mM of the peptide in the TAM region containing the phosphorylated tyrosine and 50 mM of ATP, the incubation was further effected at 30xc2x0 C. for 15 min. After the completion of the reaction, the sample was electrophoresed on a 10% agarose gel and a tyrosine kinase of 72 kDa was separated. The activation of this kinase was confirmed by examining the phosphorylation of the tyrosine moiety in the kinase per se by western blotting with the use of anti-tyrosine phosphorylation antibody. Then the extent of the phosphorylation was numerically expressed by using an image analyzer and thus the tyrosine kinase phosphorylation inhibitory ratio of the compound 101 was determined.
ii) Results of the Experiment
The results are given in Table 8.
(4) Effect of Inhibiting Activation (Phosphorylation) of Tyrosine Kinase of 72 kDa Due to Antigenic Stimulation in RBL-2H3 Cells
i) Experimental Method
RBL-2H3 cells were incubated for 10 min together with a test compound in a PBS buffer containing 0.1% of BSA and 1 mM of calcium. Next, the cells were reacted with an antigen specific for the IgE receptor for 10 min. After the completion of the antigenic stimulation, the cells were allowed to stand in ice for 1 hr in a 10 mM phosphate buffer (pH 7.5) containing a lysis buffer (1% Triton X-100, 0.1% SDS, 0.5% sodium deoxycholate, 50 mM NaCl, 50 mM NaF, 1 mM phenylmethyl sulfonyl fluoride, 50 xcexcg/ml eupeptin, 10 unit/ml aprotonin) and 0.1% of NaN3 followed by centrifugation to give a cell lysate. This lysate was diluted with a buffer for electrophoresis, heated (95xc2x0 C., 5 min) and then electrophoresed on a 10% SDS-polyacrylamide gel. After the electrophoresis, the sample was electrically transcribed onto a 0.2 xcexcm nitrocellulose membrane and treated with an anti-phosphotyrosine antibody for 1 hr. Then the inhibitory activity was evaluated by the coloring analysis through chemiluminescence.
ii) Results of the Experiment
The results are given in Table 9.
These results indicate that the compounds of the present invention would inhibit the binding of the IgE receptor xcex3 chain to the tyrosine kinase of 72 kDa and thus suppress the liberation of chemical mediators such as serotonin, histamine and leukotrienes.
Therefore, the compounds of the present invention are usable as preventives or remedies for diseases against which the effect of inhibiting binding of the IgE receptor xcex3 chain to a tyrosine kinase of 72 kDa is efficacious. More particularly speaking, the compounds of the present invention are usable as preventives or remedies for diseases caused by the liberation of chemical mediators such as serotonin, histamine and leukotrienes. Still particularly, these compounds are useful in preventing or treating allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, urticaria, hay fever, gastrointestinal allergy or food allergy.
Moreover, the compounds of the present invention are useful from the viewpoint the low toxicity and high safety thereof.
When the compounds of the present invention are used for the above-mentioned diseases, they may be administered both orally and parenterally in the dosage form of tablets, powders, granules, capsules, syrups, troches, inhalants, suppositories, injections, ointments, ophthalmic ointments, eye drops, nasal drops, ear drops, cataplasmas, lotions, etc.
The administration dose widely varies depending on the type of the disease, the severity of the symptoms, the age, sex and drug sensitivity of the patient. In general, such a compound is administered in a daily dose of from about 0.03 to 1,000 mg, preferably from 0.1 to 500 mg and still preferably from 0.1 to 100 mg once to several times a day. In the case of injections, the dose usually ranges from about 1 xcexcg/kg to 3,000 xcexcg/kg, preferably from about 3 xcexcg/kg to 1,000 xcexcg/kg.
The compounds of the present invention may be processed into preparations by conventional methods with the use of conventional pharmaceutical carriers.
Namely, solid preparations for oral administration are prepared by mixing the principal agent with fillers, binders, disintegrating agents, lubricants, coloring agents, corrigents, antioxidants, etc. and then processed into tablets, coated tablets, granules, powders, capsules, etc. by conventional methods.
Examples of the above-mentioned fillers are lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc.
Examples of the binders are polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, acacia, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin. Examples of the lubricants are magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oils, etc.
The coloring agents are those admitted to be added to medicines. Examples of the corrigents include cocoa powder, menthol, aromatic powder, peppermint oil, borneol and powdered cinnamon bark. As the antioxidants, use can be made of any pharmaceutically authorized ones such as ascorbic acid and xcex1-tocopherol. Needless to say, tablets and granules may be appropriately coated with sugar, gelatin, etc., if necessary.
Meanwhile, injections, eye drops, etc. can be prepared by blending the principal agent with, if needed, pH regulating agents, buffer agents, suspending agents, dissolution aids, stabilizers, tonicity agents, antioxidants, preservatives, etc. and then processed in a conventional manner. In such a case, it is also possible, if needed, to give freeze-dried preparations. Injections may be intravenously, hypodermically or intramuscularly administered.
Examples of the above-mentioned suspending agents include methylcellulose, Polysorbate 80, hydroxyethylcellulose, acacia, tragacanth, sodium carboxymethylcellulose and polyoxyethyelne sorbitan monolaurate.
Examples of the dissolution aids are polyoxyethylene-hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, etc.
Examples of the stabilizers usable herein include sodium sulfite, sodium metasulfite and ether. Examples of the preservatives usable herein include methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
Ointments can be produced by blending the principal agent with, if needed, stabilizers, antioxidants, preservatives, etc. and processed in a conventional manner.